Polyglutamine Disease Drpla Mouse Model To Establish The Mechanism Of Drug Treatment

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disease characterized by a number of symptoms that include ataxia, tremor, myoclonus, chorea and dementia. This disease is caused by the mutant atrophin-1 gene with an expansion of CAG repeats that encode glutamines. Mutant Atrophin-1 with polyglutamine expansion causes neuronal impairments in several brain regions, such as the dentate cerebellar nucleus, red nucleus, globus pallidus and subthalamic nucleus.To study the pathogenesis of DRPLA and to test potential therapeutic methods, we established Atro-118Q mice with neuron-specific expression of human mutant atrophin-1. These mice exhibited several neurodegenerative phenotypes that are commonly seen in the symptoms of DRPLA patients, including ataxia, tremor and other motor impairments. Nuclear inclusion bodies in neurons and somal atrophy of neurons were found in the brains of Atro-118Q mice. Overexpression of wild type Atrophin-1 could not rescue the neurodegeneration in Atro-118Q mice, indicating that mutant Atrophin-1 with polyglutamine expansion does not simply function in a dominant negative manner. Biochemical analysis of Atro-118Q mice revealed hypoacetylation of histone H3 in brain tissues and thus suggests that global gene repression is an underlying mechanism for neurodegeneration in this mouse model. Intraperitoneal administration of sodium butyrate, a histone deacetylase inhibitor, ameliorated the histone acetylation defects, significantly improved motor performance, and extended the average life span of Atro-118Q mice. These results suggest that reversion of transcription repression with small molecules such as sodium butyrate is a feasible approach to treating DRPLA symptoms, they also support the hypothesis that transcription deregulation plays an important role in the pathogenesis of polyglutamine expansion diseases.DRPLA causative gene atrophin-1 is an evolutional conserved gene involving in transcriptional regulation. We established knockout mice for atrophin-1 to study its function. These mice showed several abnormal phenotypes in brains or eyes. Further phenotypic analyses will help us elucidate the relationship among transcriptional regulator, developmental process and polyglutamine expansion diseases.